Lipid and Lipoprotein Disorders in Insulin Resistant States, Metabolic Syndrome and Type 2 Diabetes; Incretin Regulation of Intestinal Lipid and Lipoprotein Metabolism. Current areas of interest and active research in our laboratory include: Mechanistic studies of the link between diabetes and the increased risk of cardiovascular disease; Mechanisms of metabolic dyslipidemia in insulin resistant states; Regulation of Intestinal Lipid and Lipoprotein Metabolism by Gut Peptides; GLP-1 and GLP-2 signaling in the intesteine; Molecular biology of atherogenic lipoproteins and apolipoprotein B and involvement in the development of atherosclerosis; Mechanistic links between childhood obesity, insulin resistance, and the risk of development of premature atherosclerosis; mechanisms of action of hypolipidemic drugs at the cellular and molecular level.

Despite current treatments, people with diabetes continue to be affected by the long-term consequences of the disease. These long-term consequences are called complications and they include eye disease, kidney disease, nerve disease and heart disease. Kidney disease due to diabetes is the most common cause of kidney failure requiring treatment with dialysis or kidney transplantation and people with kidney disease are much more likely to also suffer from heart disease. Our lab is committed to conducting research on the causes of kidney disease in diabetes and on the links between kidney disease and heart disease. Our major research strands are: 1) Epigenetic mechanisms and related post-translational modifications; 2) Endothelial dysfunction and endothelial-podocyte interactions; 3) Re-purposing of existing therapies and exploration of the glucose-independent effects of diabetes treatments. Through this research we aim to develop new and better treatments for diabetes to reduce the burden of the condition on the millions of people affected.

Johane Allard is a Gastroenterologist and a Professor at the Department of Medicine and the Department of Nutritional Sciences at the University of Toronto. One of her main research interests is obesity and related metabolic disturbances, particularly non-alcoholic fatty liver disease (NAFLD), insulin resistance, type 2 diabetes (T2D), and metabolic syndrome. She is conducting mainly patient-based clinical research on the influence of diet, oxidative stress, fatty acids, gene expression, and intestinal microbiota on these conditions.

Later, Dr. Allard focused on patients with NAFLD without infectious disease. She demonstrated that patients with NAFLD, especially those with non-alcoholic steatohepatitis (NASH), had suboptimal dietary intakes (Da Silva et al. J Acad Nutr Diet. 2014; 114(8):1181-94and lower long-chain polyunsaturated fatty acids (Allard et al. J Hepatol 2008;48(2):300-7) and altered phospholipid composition (Arendt et et al. Appl Physiol Nutr Metab. 2013 Mar;38(3):334-40). Her group was the first to describe altered intestinal microbiota in patients with biopsy proven steatohepatitis compared to healthy controls (Mouzaki et al. Hepatology Hepatology 2013; 58(1):120-7), using polymerase chain reaction. Patients with NASH had a lower Bacteroidetes (% of total bacteria), and this was still significant after correction for body mass index and dietary fat intake. There was a trend (r = -0.31; P = 0.06) towards a negative association between the percentage of Bacteroidetes and insulin resistance. A more detailed analysis using Illumina technology in a larger sample size is currently in progress.

Dr. Allard has also entered a successful collaboration with the bariatric surgery team at the University Health Network and was awarded a CIHR operating grant examining the “Role of intestinal microbiota in non-alcoholic fatty liver disease pre and post bariatric surgery.” Together with Dr. Herbert Gaisano, she is also heading a CIHR funded team including clinical/translational researchers and basic scientist, aiming aims at “Exploiting the therapeutic effects of the fecal microbiome in bariatric care”. Goal of the team grant is to (1) Track the changes in the intestinal microbiome in morbidly obese patients undergoing bariatric surgery and determine the relationship with improvement in insulin resistance, T2D, and weight loss. (2) Pilot testing of fecal microbiota transplant of lean donors into morbidly obese patients to assess, whether this can induce beneficiall effects on insulin resistance and body weight and NAFLD. (3) Determine if fecal microbiota transplant from morbidly obese patients post-bariatric surgery can improve the in vivo parameters of insulin resistance, glucose-induced insulin synthesis, and obesity/weight loss in mice. The objective is to determine the specific candidate microbial species or genes in the mice that account for these beneficial effects.

Our laboratory performs both animal and human (all age groups) experiments. The main focus of research in my lab includes food intake regulation and glycemia; carbohydrates, sweeteners, appetite and health; proteins, amino acids and food intake; dietary control of peptide hormone and neurotransmitter metabolism; and food composition, dietary status and chronic disease. My laboratory is committed to elucidating the dietary determinants and mechanisms of glycemic control and food intake. Recent study topics include: (1) investigating the effect of milk products and novel milk products on metabolic control (glycemia and gut hormones), satiety and food intake, (2) the effect of pulses and pulse ingredients on glycemic response, subjective appetite, food intake and gut hormones, and (3) investigating the effects of high vitamin intake during pregnancy on neurotransmitter gene expression and their relationship with fat mass and insulin resistance in the Wistar rat offspring at birth, at weaning and beyond.

My research focuses on pancreatic function and insulin sensitivity in malnutrition.

I created an animal model of malnutrition and we are studying the acute and long-term effect of malnutrition on pancreatic function and insulin action. We also have performed and are currently doing clinic studies in low resource countries.

My program of research develops and evaluates community-based prevention programming for South Asian adults and adolescents living in Canada at risk for diabetes using mixed-methods designs from a socio-ecological perspective. A current project I am leading is the South Asian Adolescent Diabetes Awareness Program (SAADAP) funded by the Child and Youth Diabetes Strategy Fund by the Lawson Foundation. I am also a present fellow at the Institute of Clinical Evaluative Sciences (ICES) examining variation in the prevalence of diabetes across immigrants from the South Asian Diaspora in Ontario.

Obesity is a major global health concern and is a major risk factor for other disorders, including diabetes, hypertension, and heart disease. A complex neuronal system has evolved to maintain energy homeostasis, and also glucose homeostasis. Leptin, ghrelin, glucose, glucagon-like peptides, and insulin are known peripheral signals that act to regulate feeding and energy balance by modulating the expression of neuropeptides in the brain, specifically the hypothalamus. The afferent hormones leptin and insulin have common physiological responses and intracellular signaling mechanisms, but insulin resistance and leptin resistance are major metabolic problems, sometimes leading to type 2 diabetes. We have a strong track record of neuroendocrine research, focussing on molecular and cellular biology using hypothalamic neuronal cell models. Our research program includes studies of the regulation and signalling mechanisms in many of the neuropeptide-expressing neurons involved in energy homeostasis, and the molecular/cellular events leading to leptin/insulin resistance. Importantly, there is also a direct relationship between nutritional status and reproduction, another long-term interest of my laboratory, therefore my research program is poised to utilize all the information gained from our work to provide insight into the complex nature of integrated neuroendocrine control of basic physiology.

The main focus of research in my lab is on atherosclerosis and specifically on interactions between cells and extracellular matrix during vascular remodeling. We are investigating mechanisms of vessel wall thickening and remodeling using experimental models of arterial injury in mouse, rat and rabbit, studying the role of extracellular matrix, cell-surface integrin receptors, the novel discoidin-domain receptors and MMPs in mediating SMC responses. In collaboration with Dr. Adria Giacca, we are studying the effect of high glucose and insulin on SMC growth and matrix remodeling in atherosclerosis.

I am a transplant hepatologist and clinician-scientist using a systems biology approach to studying complications post-liver transplant. I have an extensive wet lab and bioinformatics training background, allowing me to develop a unique translational research program from the bench to the bedside.

Post-transplant Diabetes Mellitus (PTDM) has been shown to significantly compromise long-term transplant patient survival in around 25% of patients. However, its pathogenesis is poorly understood with need of further investigation to implement precisely designed preventive and therapeutic strategies. I am using a combination of Systems Biology and Machine learning approaches to understand and develop more precise strategies to optimize the prevention and management of PTDM in our liver transplant recipients, thereby improving their long-term survival.

My laboratory group recently started two projects that are related to diabetes:

1) The first project aims to understand the molecular signalling that underlies diabetes-associated microvascular structural and functional changes. Our special focus herein is on the role of microvascular sphingosine-1-phosphate signaling.

2) The second project aims to understand how heart failure affects the signalling network that ultimately controls blood glucose homeostasis. The special focus here is on the effects of TNFalpha on insulin and GLP-1 secretion.

My research focuses on health outcomes and quality of care related to diabetes. Specific interests include: 1) how neighbourhood characteristics (e.g. community design, the food environment) contribute to the prevalence of obesity and diabetes; 2) gender, socioeconomic, and regional differences in diabetes outcomes; 3) health care strategies to improve the quality of diabetes care and 4) the application of geographic analytic tools to health care planning. Much of this work is done using linkage of large secondary databases including provincial administrative health care data, population-based surveys and census, retail and other environmental data sources. Students and research fellows use epidemiological and health services research methods to study diabetes and its outcomes at a population-level.

The major interests of the Brubaker laboratory relate to the synthesis, secretion and biological activities of gut hormones and, in particular, the intestinal glucagon-like peptides, GLP-1 and GLP-2. These hormones play important roles in the regulation insulin and glucagon secretion, beta cell proliferation, intestinal growth and function, and food intake. GLP-1 mimetics are currently in use for the treatment of patients with Type 2 diabetes, while a long-acting GLP-2 analog has recently been approved for the treatment of patients with intestinal insufficiency due to short bowel. Some of the areas that are currently under investigation in the lab include:

Regulation of GLP-1 and GLP-2 synthesis and secretion by the intestine, with particular focus on dietary nutrients and intracellular signalling pathways; and

Mechanisms of action of GLP-1 and GLP-2 to stimulate beta cell and intestinal growth, respectively, with a major emphasis on the roles of novel intra- and extracellular mediators of these effects, as well as possible carcinogenic effects.

Students and fellows utilize a wide-variety of approaches to investigate the physiology and pathophysiology of the glucagon-like peptides, including normal and genetically-modified animals, cell culture and imaging approaches, in combination with tissue and cellular analyses at the mRNA and protein level

Dr. Cafazzo leads the development of technologies as a way to keep people out of hospital by allowing for self-care at home for those with chronic conditions such as diabetes, asthma, end-stage renal disease and congestive heart failure.

These strategies are aimed at helping people before their conditions become acute and medical intervention is required. The emphasis here is improving patient self-efficacy.

One such solution is bant. Designed for adolescents with Type I diabities, bant simplifies diabetes management by connecting to a glucometer via Bluetooth. It also connects teens in a secure community of peers and helps them self-manage by rewarding positive behaviour every time they use their glucometer.

Main interests are mechanisms of neural synchrony and entrainment (epilepsy), hypoglycemic seizures, and neurodegenerative processes.a) We have several projects on cellular mechanisms and local system dynamics of epilepsy, particularly the biophysics of the transition to seizure, and the role of electrotonic coupling via gap junctions. Molecular biological and cellular electrophysiological techniques are being used to measure the upregulation of gap junctions in several in vitro and in vivo seizure models. b) Hypoglycemic seizures are a major problem in juveniles with diabetes. We are studying the pathophysiology of hypoglycaemic seizures in juvenile animals both in vitro and in vivo, noting that the most severe seizures seem to be associated with mainly subcortical seizure-like EEG activity, which could also be related to the ‘dead in bed’ or sudden unexplained death sometimes noted with juvenile hypoglycemic events. Also we are examining the pathophysiology of neuronal injury which is enhanced by glucose reperfusion. Glucose reperfusion is also associated with a significant upregulation of gap junctional expression, the significance of which remains to be elucidated. However is is known that provision of nutrients to neurons requires intact astrocytic gap junctional communication.

Current research interests in type 1 diabetes mellitus include the physiology of renal hyperfiltration in diabetic nephropathy, cardiorenal interactions and endothelial function, the effect of pharmaceutical agents on the urinary proteome, and functional gene polymorphisms in humans.

I am engaged in research related to psychosocial adjustment to diabetes, particularly risk for eating disorders and depression. I collaborate with Dr. Denis Daneman at Hospital for Sick Children, and we are conducting a longitudinal study of eating disturbances, depression, psychosocial functioning and medical status in girls and women with type 1 diabetes.

Research in my lab focuses on the relationship between diet, gut microbiota and health. We have been focusing on the establishment of the intestinal barrier and the role played by the gut microbiota in its regulation, at the transcriptional and post-transcriptional gene expression level. Building on recent findings linking gut microbiota, intestinal barrier and the metabolic syndrome, we are now expanding our research to understand how the establishment of the gut microbiota in early life may be linked to developing this condition in later life.

The research interests of the laboratory are in the study of patients at risk for Type 2 Diabetes or at risk for the complications of diabetes and identifying serum biomarkers that will predict patient outcomes. The most recent focus has been on the adipokine adiponectin and on the enzyme paraoxonase-1 (PON1). Adiponectin is an insulin-sensitizing protein produced by adipocytes.PON1 is an anti-inflammatory component of high density lipoproteins. We have studied these factors in four patient groups:1) The Sandy Lake Oji-Cree; 2) women at risk for post-gestational diabetes; 3) patients with renal failure on dialysis; and 4) renal transplant recipients.